The Hippo tumor suppressor pathway plays a crucial role in regulating organ size by inhibiting cell proliferation and promoting apoptosis, and limitin stem/progenitor cell self- renewal and expansion. The YAP/TAZ transcription co-activators are the major downstream effectors of the Hippo pathway. Despite extensive studies, upstream signals regulating the Hippo pathway are unknown. Currently, no extracellular ligand or cell surface receptor has been identified to regulate the mammalian Hippo-YAP. Our preliminary studies have discovered that lysophosphatidic acid (LPA) and sphingosine 1- phosphophate (S1P) are important signaling molecules that regulating the Hippo pathway. LPA and S1P act through their respective G-protein coupled receptors (GPCRs) to activate YAP. Both LPA and S1P have been implicated in cancer development and metastasis. Notably, activating mutations of Gq/11 are frequently found (83%) in uveal melanoma, which is the most common intraocular tumor in the eye with strong propensity of metastasis into the liver. Our preliminary study showed that active Gq/11 potently stimulates YAP activity. The major goals of this proposal are to investigate the mechanism of Hippo-YAP regulation by GPCR and to determine the functional significance of YAP/TAZ activation in the biology of LPA, S1P and other extracellular signals. Moreover, we will investigate the pathophysiological function of YAP/TAZ activation in the development of uveal melanoma and aim to provide scientific basis for treatment of this disease. PUBLIC HEALTH RELEVANCE: The Hippo signaling pathway plays a major role in organ size regulation by controlling cell number and has also been implicated in human cancer. Preliminary studies from the PI's laboratory have identified the first extracellular signals and cell surface receptors that regulate the Hippo pathway, and suggested a critical role of the Hippo pathway in uveal melanoma, which is the most common intraocular tumor in the eye. The goal of this proposal is to gain knowledge of Hippo-YAP pathway regulation and its role in uveal melanoma development.